A central paradox in transforming growth factor beta (TGF-b) biology is how the same growth factor can induce such divergent responses as growth stimulation (e.g., mesenchymal cells) and growth inhibition (e.g., epithelial cells). Considering the pivotal role TGF-b has in a number of normal and pathological conditions, addressing that issue is fundamental if we hope to be able to develop specific intervention strategies. To that end, during the previous funding cycle we have determined that receptor elements and activity differentially regulate TGF-b receptor (TGF-bR) endocytosis depending upon the cell type. However, it is presently unclear how this endocytic response is coupled to receptor signaling and subsequently cellular phenotypes. Two polarized views state that (i)endocytosis is simply a means to dampen the response - all signaling is initiated and completed at the plasma membrane; or (ii) the endocytic system is required to promote the association of activated receptors with downstream signaling molecules. While these extreme viewpoints make for lively discussion, a more appropriate question would be: are these models mutually exclusive or is it possible to have aspects of each occurring in various cell types and/or receptor systems? In this competing renewal we wish to test the general hypothesis that the endocytosis and/or trafficking of TGF-bRs is controlled by defined receptor elements and regulates association with distinct signaling intermediaries in polarized and nonpolarized cells. Preliminary data is presented documenting specific association of TGFbRs with the b2 subunit ofAP2, a requirement for TGF-bR internalization in Smad2 phsosphorylation, and polarized TGF-bR trafficking and signaling. We will further extend this concept of an integrated action of the endocytic and signaling machineries in distinct cell types by (i) characterizing the interaction and functional significance of TGF-bRs with the plasma membrane AP2 complex in fibroblasts and epithelial cells; (ii) defining the relationship between TGF-bR endocytosis and signaling in various cell types; and (iii) identifying the receptor elements regulating basolateral TGF-bR sorting and determining whether this polarized membrane location differentially engages the signaling and endocytic machinery.